Thiazole compounds useful as inhibitors of protein kinase

ABSTRACT

The present invention provides a compound of formula I:  
                 
 
     or a pharmaceutically acceptable derivative thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK3, Aurora2, and Syk mammalian protein kinases. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional PatentApplication No. 60/295,158 filed Jun. 1, 2001, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds that are proteinkinase inhibitors, pharmaceutically acceptable compositions comprisingsaid compounds, and methods of use thereof. More particularly, thecompounds are inhibitors of GSK-3, Aurora2, and Syk protein kinases andare useful for treating, or lessening the severity of, a variety ofdiseases and conditions, such as diabetes, Alzheimer's disease, stroke,proliferative disorders, and asthma.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided inrecent years by better understanding of the structure of enzymes andother biomolecules associated with target diseases. One important classof enzymes that has been the subject of extensive study is the proteinkinases.

[0004] Protein kinases mediate intracellular signal transduction. Theydo this by affecting a phosphoryl transfer from a nucleosidetriphosphate to a protein acceptor that is involved in a signalingpathway. There are a number of kinases and pathways through whichextracellular and other stimuli cause a variety of cellular responses tooccur inside the cell. Examples of such stimuli include environmentaland chemical stress signals (e.g. osmotic shock, heat shock, ultravioletradiation, bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1(IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g.granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF). An extracellular stimulus may effect oneor more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis and regulation of cell cycle.

[0005] Many diseases and conditions are associated with abnormalcellular responses triggered by protein kinase-mediated events. Thesediseases include autoimmune diseases, inflammatory diseases,neurological and neurodegenerative diseases, cancer, cardiovasculardiseases, allergies and asthma, Alzheimer's disease or hormone-relateddiseases. Accordingly, there has been a substantial effort in medicinalchemistry to find protein kinase inhibitors that are effective astherapeutic agents.

[0006] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine proteinkinase comprised of α and β isoforms that are each encoded by distinctgenes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim andKimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These include glycogen synthase which is the rate limitingenzyme necessary for glycogen synthesis, the microtubule associatedprotein Tau, the gene transcription factor β-catenin, the translationinitiation factor e1F2B, as well as ATP citrate lyase, axin, heat shockfactor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverse targetsimplicate GSK-3 in many aspects of cellular metabolism, proliferation,differentiation and development.

[0007] In a GSK-3 mediated pathway that is relevant for the treatment oftype II diabetes, insulin-induced signaling leads to cellular glucoseuptake and glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

[0008] GSK-3 activity has also been associated with Alzheimer's disease.This disease is characterized by the well-known β-amyloid peptide andthe formation of intracellular neurofibrillary tangles. Theneurofibrillary tangles contain hyperphosphorylated Tau protein whereTau is phosphorylated on abnormal sites. GSK-3 has been shown tophosphorylate these abnormal sites in cell and animal models.Furthermore, inhibition of GSK-3 has been shown to preventhyperphosphorylation of Tau in cells [Lovestone et al., Current Biology4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)].Therefore, it is believed that GSK-3 activity may promote generation ofthe neurofibrillary tangles and the progression of Alzheimer's disease.

[0009] Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

[0010] Aurora-2 is a serine/threonine protein kinase that has beenimplicated in human cancer, such as colon, breast and other solidtumors. This kinase is involved in protein phosphorylation events thatregulate the cell cycle. Specifically, Aurora-2 plays a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, the aurora-2 proteinhas been found to be overexpressed [Bischoff et al., EMBO J., 17,3052-3065 (1998); Schumacher et al., J. Cell Biol., 143, 1635-1646(1998); Kimura et al., J. Biol. Chem., 272, 13766-13771 (1997)].

[0011] Syk is a tyrosine kinase that plays a critical role in FcεRImediated mast cell degranulation and eosiniphil activation. Accordingly,Syk kinase is implicated in various allergic disorders, in particularasthma.

[0012] It has been shown that Syk binds to the phosphorylated gammachain of the FcεR1 receptor via N-terminal SH2 domains and is essentialfor downstream signaling [Taylor et al, Mol Cell Biol 1995; 15:4149].

[0013] Inhibition of eosinophil apoptosis has been proposed as keymechanisms for the development of blood and tissue eosinophilia inasthma. IL-5 and GM-CSF are upregulated in asthma and are proposed tocause blood and tissue eosinophilia by inhibition of eosinophilapoptosis. Inhibition of eosinophil apoptosis has been proposed as a keymechanism for the development of blood and tissue eosinophilia inasthma. It has been reported that Syk kinase is required for theprevention of eosinophil apoptosis by cytokines (usingantisense)[Yousefi et al,

[0014] J Exp Med 1996;183:1407].

[0015] The role of Syk in FcyR dependent and independent response inbone marrow derived macrophages has been determined by using irradiatedmouse chimeras reconstituted with fetal liver cells from Syk −/−embryos. Syk deficient macrophages were defective in phagocytosisinduced by FcγR but showed normal phagocytosis in response to complement[Kiefer et al, Mol Cell Biol 1998; 18:4209]. It has also been reportedthat aerosolized Syk antisense suppresses Syk expression and mediatorrelease from macrophages [Stenton et al, J Immunology 2000; 164: 3790].

[0016] Considering the lack of currently available treatment options forthe majority of the conditions associated with protein kinases,especially GSK-3, Aurora-2, and Syk, there is still a great need for newtherapeutic agents that inhibit these protein targets.

SUMMARY OF THE INVENTION

[0017] The present invention addresses this need by providing a compoundof formula I:

[0018] or a pharmaceutically acceptable derivative thereof, wherein R¹and Ar¹ are as defined below.

[0019] The present invention also provides a pharmaceutically acceptablecomposition comprising a compound of formula I.

[0020] The compounds and pharmaceutically acceptable compositions of thepresent invention are useful as inhibitors of GSK-3, Aurora-2, and Sykprotein kinases. Thus, they are also useful in methods for treating orlessening the severity of a variety of disorders, such as allergicdiseases, proliferative disorders, cancer, neurodegenerative disorders,and diabetes.

DESCRIPTION OF THE INVENTION

[0021] The present invention relates to a compound of formula I:

[0022] or a pharmaceutically acceptable derivative thereof, wherein:

[0023] R¹ is selected from R, halogen, CN, NO₂, or TR;

[0024] T is an optionally substituted C₁-C₄ alkylidene chain wherein upto two methylene units of T are optionally and independently replaced byO, N(R), C(O), S, SO, or SO₂;

[0025] each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein:

[0026] two R bound to the same nitrogen atom are optionally takentogether with the nitrogen to form a 3-7 membered saturated, partiallyunsaturated, or fully unsaturated ring having 0-2 heteroatoms, inaddition to the nitrogen bound thereto, independently selected fromnitrogen, oxygen, or sulfur;

[0027] Ar¹ is an optionally substituted ring selected from:

[0028] (a) a 3-8 membered monocyclic or 8-10 membered bicyclicsaturated, partially unsaturated, or aryl ring;

[0029] (b) a 3-7 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or

[0030] (c) a 5-6 membered monocyclic or 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein:

[0031] Ar¹ is optionally substituted by one to four substituentsselected from the group consisting of:

[0032] (a) one group selected from QR, Ar², or QAr²; and

[0033] (b) up to four R² groups;

[0034] each Q is indpendently selected from a valence bond or anoptionally substituted C₁₋₆ alkylidene chain, wherein:

[0035] one or two non-adjacent methylene units of Q are optionally andindependently replaced by —O—, —S—, —NR—, —C(O)—, —CO₂—, —C(O)NR—,—OC(O)NR—, —C(O)C(O)—, —C(O)C(O)—, —NRC(O)—, NRCO₂—, —NRC(O)NR—, —S(O)—,—SO₂—, —NRSO₂—, —SO₂NR—, or —NRSO₂NR—;

[0036] each Ar² is an optionally substituted ring independently selectedfrom:

[0037] (a) a 3-8 membered monocyclic or 8-10 membered bicyclicsaturated, partially unsaturated, or aryl ring;

[0038] (b) a 3-7 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or

[0039] (c) a 5-6 membered monocyclic or 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein:

[0040] Ar² is optionally substituted by one to four R² groups; and

[0041] each R² is independently selected from R, halogen, NO₂, CN, OR,SR, N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂, OC(O)N(R)₂,SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, or C(O)CH₂C(O)R;wherein:

[0042] two R² on adjacent positions on Ar¹ or Ar² are optionally takentogether to form a saturated, partially unsaturated, or fullyunsaturated 4-6 membered ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

[0043] As used herein, the following definitions shall apply unlessotherwise indicated.

[0044] The phrase “optionally substituted” is used interchangeably withthe phrase “substituted or unsubstituted.” Unless otherwise indicated,an optionally substituted group may have a substituent at eachsubstitutable position of the group, and each substitution isindependent of the other.

[0045] The term “aliphatic” or “aliphatic group” as used herein means astraight-chain or branched C₁-C₈ hydrocarbon chain that is completelysaturated or that contains one or more units of unsaturation, or amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (also referred to herein as “carbocycle” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3-7 members. For example, suitable aliphatic groups include, but are notlimited to, linear or branched or alkyl, alkenyl, alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

[0046] The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety include bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms.

[0047] The term “heteroatom” means nitrogen, oxygen, or sulfur andincludes any oxidized form of nitrogen and sulfur, and the quaternizedform of any basic nitrogen. Also the term “nitrogen” includes asubstitutable nitrogen of a heterocyclic ring. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

[0048] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring”. The term “aryl”also refers to heteroaryl ring systems as defined hereinbelow.

[0049] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic or tricyclic ringsystems having five to fourteen ring members in which one or more ringmembers is a heteroatom, wherein each ring in the system contains 3 to 7ring members.

[0050] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic,bicyclic and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic, atleast one ring in the system contains one or more heteroatoms, andwherein each ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

[0051] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like)or heteroaryl (including heteroaralkyl and heteroarylalkoxy and thelike) group may contain one or more substituents. Suitable substituentson the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, orheteroaralkyl group are selected from halogen, —R^(o), —OR^(o), —SR^(o),1,2-methylene-dioxy, 1,2-ethylenedioxy, phenyl (Ph) optionallysubstituted with R^(o), —O(Ph) optionally substituted with R^(o),—CH₂(Ph) optionally substituted with R^(o), —CH₂CH₂(Ph), optionallysubstituted with R^(o), —NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o),—NR^(o)C(O)N(R^(o))₂, —NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o),—NR^(o)NR^(o)C(O)N(R^(o))₂, —NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o),—C(O)CH₂C(O)R^(o), —CO₂R^(o), —C(O)R^(o), —C(O)N(R^(o))₂,—OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂, —S(O)R^(o),—NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C(═NH)—N(R^(o))₂, or —(CH₂)_(y)NHC(O)R^(o), wherein each R^(o) isindependently selected from hydrogen, optionally substituted C₁₋₆aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclicring, phenyl, —O(Ph), or —CH₂(Ph). Optional substituents on thealiphatic group of R^(o) are selected from NH₂, NH(C₁₋₄ aliphatic),N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂,CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic), or halo C₁₋₄aliphatic.

[0052] An aliphatic group or a non-aromatic heterocyclic ring maycontain one or more substituents. Suitable substituents on the saturatedcarbon of an aliphatic group or of a non-aromatic heterocyclic ring areselected from those listed above for the unsaturated carbon of an arylor heteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic. Optional substituents on the aliphatic group of R* areselected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic),O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).

[0053] Optional substituents on the nitrogen of a non-aromaticheterocyclic ring are selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, optionally substituted phenyl, optionallysubstituted —O(Ph), optionally substituted —CH₂(Ph), optionallysubstituted —CH₂CH₂(Ph), or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring. Optional substituents on the aliphatic group or thephenyl ring of R+are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN,CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄aliphatic).

[0054] The term “alkylidene chain” refers to a straight or branchedcarbon chain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

[0055] A combination of substituents or variables is permissible only ifsuch a combination results in a stable or chemically feasible compound.A stable compound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

[0056] It will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention.

[0057] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools or probes in biological assays.

[0058] According to one embodiment, the present invention relates to acompound of formula I:

[0059] or a pharmaceutically acceptable derivative thereof, wherein R¹and Ar¹ are as defined above, provided that: when Ar¹ is phenyl with twoR² substituents, then the two R² are not simultaneously OR in the metaand para positions of Ar¹.

[0060] According to another embodiment, the present invention relates toa compound of formula I:

[0061] or a pharmaceutically acceptable derivative thereof, wherein R¹and Ar¹ are as defined above, provided that: R¹ is other than CN.

[0062] Preferred Ar¹ groups of formula I are optionally substitutedrings selected from:

[0063] (a) a phenyl, indanyl, or naphthyl ring;

[0064] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or

[0065] (c) a 5-6 membered monocyclic or 9-10 membered bicyclicheteroaryl ring having 1-2 heteroatoms independently selected fromoxygen, nitrogen, or sulfur.

[0066] More preferred Ar¹ groups of formula I are rings selected from:

[0067] (a) a phenyl, indanyl, or naphthyl ring;

[0068] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or

[0069] (c) a 5-6 membered monocyclic heteroaryl ring having 1-2nitrogens, wherein:

[0070] Ar¹ is substituted by one to four substituents selected from thegroup consisting of:

[0071] (a) one group selected from QR, Ar², or QAr²; and

[0072] (b) up to four R² groups.

[0073] Most preferred Ar¹ rings are selected from substituted phenyl,indanyl, naphthyl, pyrimidinyl, or pyridyl. Preferred R² substituents onAr¹ are halogen, CN, CO₂R, R, NO₂, OR, haloalkyl, SO₂N(R)₂, or N(R)₂.More preferred R² substituents on Ar¹ are fluoro, iodo, chloro, bromo,CO₂CH₃, methyl, ethyl, t-butyl, NH₂, NHMe, N(Me)₂, OH, OCH₃, OCH₂CH₃,CF₃, SO₂NH₂, or SO₂NHMe. Other preferred compounds include those wheretwo R are taken together to form a methylenedioxy or an ethylenedioxysubstituent.

[0074] Preferred QR or QAr² substituents on Ar¹ of formula I are thosewherein Q is a C₁₋₄ alkylidene chain wherein one or two methylene unitsof Q are optionally replaced by O, NR, NRCO, NRCO₂, NRSO₂, or CONR,wherein each R is hydrogen or an optionally substituted C₁₋₄ aliphaticgroup and wherein Ar² is a 3-6 membered carbocyclic ring or anoptionally substituted phenyl, 5-6 membered heterocyclic, or heteroarylring having one to two heteroatoms independently selected from nitrogen,oxygen, or sulfur.

[0075] The Ar² group of the QAr² moiety of formula I is optionallysubstituted with R, OR, N(R)₂, SO₂R, halogen, NO₂, CN, SR, SO₂N(R)₂,CO₂R, C(O)R, or oxo. More preferred QAr² groups of formula I areselected from O(CH₂)₃pyrrolidin-1-yl, O(CH₂)₂morpholin-4-yl,O(CH₂)₃(4-hydroxyethylpiperazin-1-yl), O(CH₂)₃piperazin-1-yl,O(CH₂)₃(4-hydroxymethylpiperidin-1-yl),O(CH₂)₃(4-hydroxypiperidin-1-yl), NHCOCH₂pyridin-2-yl,NHCOCH₂(2-aminothiazol-4-yl), NHCOCH₂cyclopropyl,NHCO(CH₂)₂(piperazin-2,5-dione-3-yl), NHCOpyrrolidin-1-yl,NHCOmorpholin-4-yl, NHCO₂CH₂tetrahydrofuran-2-yl,NHCO₂tetrahydrofuran-2-yl, NHCO₂tetrahydropyran-4-yl,NHCO₂CH₂tetrahydropyran-2-yl, Ophenyl, OCH₂(cyclohexyl), OCH₂phenyl,OCH₂ (3-CN-phenyl), OCH₂ (2-NO₂-phenyl), OCH₂ (3-NH₂-phenyl),OCH₂(4-CO₂R-phenyl), OCH₂-pyridyl, OCH₂(mono-, di-, or tri-halogenatedphenyl), OCH₂(C₁-C₆ aliphatic substituted phenyl), OCH₂CH₂-pyrrolyl,OCH₂-pyrrolyl, and OCH₂(phenyl substituted with one or two R²)

[0076] Preferred Ar² substituents on Ar¹ of formula I are optionallysubstituted rings selected from:

[0077] (a) a phenyl, indanyl, or naphthyl ring;

[0078] (b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or

[0079] (c) a 5-6 membered monocyclic or 9-10 membered bicyclicheteroaryl ring having 1-2 heteroatoms independently selected fromoxygen, nitrogen, or sulfur, wherein:

[0080] Ar² is optionally substituted with 1-2 R² groups.

[0081] More preferred Ar² substituents on Ar¹ of formula I areoptionally substituted rings selected from phenyl, pyridyl, indolyl,naphthyl, or benzo[1,3]dioxolyl.

[0082] Preferred R² groups, when present, on the Ar² substituent on Ar¹of formula I are selected from R, halogen, NO₂, CN, OR, SR, N(R)₂,C(O)R, SO₂N(R)₂, or SO₂R. More preferred R² groups, when present, on theAr² substituent on Ar¹ of formula I are selected from methyl, ethyl,t-butyl, fluoro, chloro, bromo, CF₃, OMe, OEt, CN, SO₂Me, SO₂NH₂, NH₂,NHMe, N(Me)₂, SMe, SEt, OH, C(O)Me, NO₂, or CH₂OH.

[0083] One embodiment of this invention relates to a compound of formulaIa:

[0084] or a pharmaceutically acceptable derivative thereof, wherein Ar¹is as defined above.

[0085] Preferred Ar¹ groups of formula Ia are those described above forformula I.

[0086] Another embodiment of this invention relates to a compound offormula II:

[0087] or a pharmaceutically acceptable derivative thereof, wherein R²is as defined above.

[0088] Preferred R² groups of formula II are those defined above forformula I and include those where two R² are taken together to form amethylenedioxy or an ethylenedioxy substituent.

[0089] A preferred embodiment of this invention relates to a compound offormula IIa or IIa′:

[0090] or a pharmaceutically acceptable derivative thereof, wherein QR,QAr² and R² are as defined above.

[0091] Preferred R² groups of formula IIa or IIa′ are those describedabove for compounds of formula I.

[0092] Preferred QR and QAr² groups of formula IIa or IIa′ are thosedescribed above for compounds of formula I.

[0093] Another preferred embodiment relates to a compound of formulaIII:

[0094] or a pharmaceutically acceptable derivative thereof, wherein R¹,R², and QAr² are as defined above.

[0095] Preferred R² and QAr² groups of formula III are those describedabove for formula I.

[0096] Preferred R¹ groups of formula III are selected from hydrogen,N(R)₂, SR, OR, or TR. More preferred R¹ groups are selected from OH,OCH₃, CH₂OH, CH₂OCH₃, CH₂NH₂, or CH₂NHCH₃.

[0097] Another preferred embodiment relates to a compound of formula IV:

[0098] or a pharmaceutically acceptable derivative thereof, wherein R²and Ar² are as defined above.

[0099] Preferred R² and Ar² groups of formula IV are those describedabove for compounds of formula I.

[0100] Exemplary structures of formula I are set forth in Table 1 below.TABLE 1 Compounds of Formula I Cmpd I- Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

— — 33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

— — 103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

[0101] Exemplary structures of formulae IIa and IIa′ are set forth inTable 2 below. TABLE 2 Compounds of Formulae IIa and IIa′ IIa-1

IIa-2

IIa-3

IIa-4

IIa-5

IIa-6

IIa-7

IIa-8

IIa-9

IIa-10

IIa-11

IIa-12

IIa-13

IIa-14

IIa-15

IIa-16

IIa-17

IIa-18

IIa-19

IIa-20

IIa-21

IIa-22

IIa-23

IIa-24

IIa-25

IIa-26

IIa-27

IIa-28

IIa-29

IIa-30

IIa-31

IIa-32

IIa-33

IIa-34

IIa-35

IIa-36

IIa-37

IIa-38

IIa-39

IIa-40

IIa-41

IIa-42

IIa-43

IIa-44

IIa-45

IIa-46

IIa-47

IIa-48

IIa-49

IIa-50

[0102] The present compounds may be prepared in general by methods knownto those skilled in the art for analogous compounds, as illustrated bythe general Scheme I and the synthetic examples shown below.

[0103] Reagents and conditions: (a) DMF-DMA, THF, 12-18 hours, roomtemperature; (b) H₂NCN, 4N HCl in dioxane, 12-18 hours, 120° C.; (c)Ethanol, reflux, 12-18 hours.

[0104] Scheme I above shows a general synthetic route that may be usedused for preparing compounds of formula I.

[0105] In step (a), a solution of 2-acetyl thiazole (1) in THF istreated with dimethylformamide-dimethylacetal and the resulting mixturestirred at room temperature over night. The reaction mixture isconcentrated in vacuo and the concentrate triturated with diethyl etherto afford 2.

[0106] To prepare intermediate 4 from aniline 3 in step (b), a mixtureof 3 and cyanamide in HCl (4N in dioxane) is heated at 120° C.overnight. After cooling to room temperature, aqueous work-up affordsthe desired guanidine compound 4. One of skill in the art wouldrecognize that a wide variety of aryl guanidines may be prepared at step(b) and, thus, be used to prepare compounds of formula I with a widevariety of Ar¹ rings.

[0107] In step (c), guanidine 4 is combined with enaminone 2 in ethanolin a sealed tube. The resulting mixture is heated at reflux overnightthen concentrated and the crude product purified by columnchromatography to afford the desired pyrimidine compound 5. The detailsof the conditions used for producing these compounds are set forth inthe Examples.

[0108] The activity of a compound utilized in this invention as aninhibitor of GSK3, Aurora2, or Syk protein kinase may be assayed invitro, in vivo or in a cell line according to methods known in the artand by the methods set forth in the Examples below. In vitro assaysinclude assays that determine inhibition of either the phosphorylationactivity or ATPase activity of activated GSK3, Aurora2, or Syk proteinkinase. Alternate in vitro assays quantitate the ability of theinhibitor to bind to GSK3, Aurora2, or Syk protein kinase. Inhibitorbinding may be measured by radiolabelling the inhibitor prior tobinding, isolating the inhibitor/GSK3, inhibitor/Aurora2, orinhibitor/Syk complex and determining the amount of radiolabel bound.Alternatively, inhibitor binding may be determined by running acompetition experiment where new inhibitors are incubated with GSK3,Aurora2, or Syk protein kinase bound to known radioligands. Detailedconditions for assaying a compound utilized in this invention as aninhibitor of GSK3, Aurora2, or Syk protein kinase are set forth in theExamples below.

[0109] According to another embodiment, the present invention provides acomposition, or pharmaceutically acceptable composition, comprising acompound of this invention or a pharmaceutically acceptable derivativethereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The amount of compound in the compositions of this invention is suchthat is effective to detectably inhibit a protein kinase, particularlyGSK3, Aurora2, or Syk protein kinase, in a biological sample or in apatient. Preferably the composition of this invention is formulated foradministration to a patient in need of such composition. Mostpreferably, the composition of this invention is formulated for oraladministration to a patient.

[0110] The term “patient”, as used herein, means an animal, preferably amammal, and most preferably a human.

[0111] The term “pharmaceutically acceptable carrier, adjuvant, orvehicle” refers to a non-toxic carrier, adjuvant, or vehicle that doesnot destroy the pharmacological activity of the compound with which itis formulated. Pharmaceutically acceptable carriers, adjuvants orvehicles that may be used in the compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

[0112] The term “detectably inhibit”, as used herein means a measurablechange in GSK3, Aurora2, or Syk protein kinase activity between a samplecomprising said composition and a GSK3, Aurora2, or Syk protein kinaseand an equivalent sample comprising GSK3, Aurora2, or Syk protein kinasein the absence of said composition.

[0113] A “pharmaceutically acceptable derivative” means any non-toxicsalt, ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof. As used herein,the term “inhibitorily active metabolite or residue thereof” means thata metabolite or residue thereof is also an inhibitor of a GSK3, Aurora2,or Syk protein kinase.

[0114] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0115] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺ (C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0116] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

[0117] For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

[0118] The pharmaceutically acceptable compositions of this inventionmay be orally administered in any orally acceptable dosage formincluding, but not limited to, capsules, tablets, aqueous suspensions orsolutions. In the case of tablets for oral use, carriers commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0119] Alternatively, the pharmaceutically acceptable compositions ofthis invention may be administered in the form of suppositories forrectal administration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0120] The pharmaceutically acceptable compositions of this inventionmay also be administered topically, especially when the target oftreatment includes areas or organs readily accessible by topicalapplication, including diseases of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas or organs.

[0121] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0122] For topical applications, the pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, the pharmaceuticallyacceptable compositions can be formulated in a suitable lotion or creamcontaining the active components suspended or dissolved in one or morepharmaceutically acceptable carriers. Suitable carriers include, but arenot limited to, mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

[0123] For ophthalmic use, the pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

[0124] The pharmaceutically acceptable compositions of this inventionmay also be administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, fluorocarbons, and/orother conventional solubilizing or dispersing agents.

[0125] Most preferably, the pharmaceutically acceptable compositions ofthis invention are formulated for oral administration.

[0126] The amount of the compounds of the present invention that may becombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, the compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions.

[0127] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

[0128] Depending upon the particular condition, or disease, to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated”.

[0129] For example, in the treatment of diabetes other anti-diabeticagents may be combined with the compounds of this invention to treatdiabetes. These agents include, without limitation, insulin ininjectable or inhalation form, insulin analogues, glitazones, sulfonylureas, alpha glucosidase inhibitors, biguamides, and insulinsensitizers.

[0130] Other examples of agents the inhibitors of this invention mayalso be combined with include, without limitation: chemotherapeuticagents such as Gleevec™, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives; treatments for Alzheimer's Disease such asAricept® and Excelon® ; treatments for Parkinson's Disease such asL-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine,pergolide, trihexephendyl, and amantadine; agents for treating MultipleSclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®),Copaxone®, and mitoxantrone; treatments for asthma such as albuterol andSingulair; agents for treating schizophrenia such as zyprexa, risperdal,seroquel, and haloperidol; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

[0131] The amount of additional therapeutic agent present in thecompositions of this invention will be no more than the amount thatwould normally be administered in a composition comprising thattherapeutic agent as the only active agent. Preferably the amount ofadditional therapeutic agent in the presently disclosed compositionswill range from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent.

[0132] According to another embodiment, the invention relates to amethod of inhibiting GSK3 protein kinase activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

[0133] According to another embodiment, the invention relates to amethod of inhibiting Aurora2 protein kinase activity in a biologicalsample comprising the step of contacting said biological sample with acompound of this invention, or a composition comprising said compound.

[0134] According to another embodiment, the invention relates to amethod of inhibiting Syk protein kinase activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

[0135] The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

[0136] Inhibition of GSK3, Aurora2, or Syk protein kinase activity in abiological sample is useful for a variety of purposes that are known toone of skill in the art. Examples of such purposes include, but are notlimited to, blood transfusion, organ-transplantation, biologicalspecimen storage, and biological assays.

[0137] According to another embodiment, the invention provides a methodfor treating or lessening the severity of a GSK3-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

[0138] The term “GSK3-mediated disease” or “GSK3-mediated condition”, asused herein, means any disease or other deleterious condition in whichGSK3 protein kinase is known to play a role. Such conditions include,without limitation, diabetes, neurodegenerative disorders, Alzheimer'sdisease, Huntington's, Parkinson's, AIDS associated dementia,amyotrophic lateral sclerosis (AML), multiple sclerosis (MS),schizophrenia, stroke, cardiomycete hypertrophy, and baldness.

[0139] According to another embodiment, the invention provides a methodfor treating or lessening the severity of an Aurora2-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

[0140] The term “Aurora2-mediated disease” or “Aurora2-mediatedcondition”, as used herein, means any disease or other deleteriouscondition in which Aurora2 protein kinase is known to play a role. Suchconditions include, without limitation, cancers such as colon and breastcancer.

[0141] According to another embodiment, the invention provides a methodfor treating or lessening the severity of a Syk-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

[0142] The term “Syk-mediated disease” or “Syk-mediated condition”, asused herein, means any disease or other deleterious condition in whichSyk protein kinase is known to play a role. Such conditions include,without limitation, allergic disorders, especially asthma.

[0143] In an alternate embodiment, the methods of this invention thatutilize compositions that do not contain an additional therapeuticagent, comprise the additional step of separately administering to saidpatient an additional therapeutic agent. When these additionaltherapeutic agents are administered separately they may be administeredto the patient prior to, sequentially with or following administrationof the compositions of this invention.

[0144] In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Example 1

[0145]

[0146] 3-Dimethylamino-1-thiazol-2-yl-propenone (2):

[0147] To a solution of 2-acetylthiazole (500 mg, 3.93 mmol) in 2 mL ofTHF was added dimethylformamide-dimethylacetal (1.6 ml, 7.86 mmol) andthe resulting solution was stirred at room temperature overnight. Thereaction mixture was evaporated and the residue triturated with ethylacetate and the product isolated by filtration. The filtered solid waswashed with diethyl ether and dried to afford 2 (400 mg) as a yellowsolid.

Example 2

[0148]

[0149] N-(3-Benzyloxy-phenyl)-guanidine (4):

[0150] 3-benzyloxy aniline (1 g, 5 mmol) and cyanamide (420 mg, 10 mmol)were dissolved in 4 mL of 4N HCl in dioxane and heated to 120° C.overnight. The reaction mixture was cooled to room temperature, quenchedwith water, and extracted with diethyl ether. The aqueous layer was madebasic with 2N NaOH and extracted thrice with dichloromethane. Theorganic extracts were combined and washed with brine, dried over MgSO₄,and concentrated to afford 4 (450 mg) as a light brown solid.

Example 3

[0151]

[0152] (3-Benzyloxy-phenyl)-(4-thiazol-2-yl-pyrimidin-2-yl)-amine (I-7):

[0153] A solution of 3-benzyloxy guanidine 4 (50 mg, 0.20 mmol) andenaminone 2 (50 mg, 0.27 mmol) in ethanol (3 mL) was heated at reflux ina sealed tube overnight. The reaction mixture was concentrated and theresidue purified by column chromatography to afford compound I-7 (20mg). M+1 (obs) 347.1. R_(t)=4.28 minutes.

Example 4

[0154] We have prepared other compounds of formula I by methodssubstantially similar to those described in the above Examples 1-3 andthose illustrated in Scheme I. The characterization data for thesecompounds is summarized in Table 3 below and includes LC/MS (M+1observed), HPLC, and ¹HNMR data.

[0155] The term “R_(t)(min)” refers to the retention time, in minutes,associated with the compound using the following HPLC method. The R_(t)was determined using a Waters ODS-AQ (2×50 mm) column at ambienttemperature with a gradient of 10→90% CH₃CN in water over 5 minutes andwith the absorbance detected as an average of 190-380 nM@4 nMincrements.

[0156] The term “Y” designates that ¹HNMR data was obtained and found tobe consistant with the assigned structure. Compound numbers correspondto the compound numbers listed in Table 1. TABLE 3 Characterization Datafor Selected Compounds of Formula I Compound No M + 1 (obs) R_(t)(min)¹H NMR I-16 300.0 3.15 — I-19 273.0 3.18 — I-22 289.0 3.47 — I-28 290.02.76 — I-31 381.0 3.66 — I-34 334.8 3.54 — I-37 323.0 3.56 — I-40 300.03.19 — I-43 273.0 3.1 — I-46 289.0 3.19 — I-49 291.0 3.33 — I-52 305.03.62 — I-55 334.0 2.16 — I-58 309.0 3.60 — I-61 322.9 2.99 — I-64 291.02.67 — I-67 269.0 3.28 — I-73 283.0 3.53 — I-10 361.1 3.76 — I-13 347.03.82 — I-4 347.1 4.14 — I-7 361.1 4.28 — I-25 285.0 2.98 — I-76 367.24.53 — I-79 386.1 3.58 — I-82 419.1 3.80 — I-85 397.1 3.94 — I-88 395.14.11 — I-100 379.1 3.85 — I-103 397.1 3.98 — I-106 429.1 4.13 — I-109379.1 3.84 — I-112 429.0 4.40 — I-115 375.2 3.96 — I-2 429.0 4.38 — I-5439.1 3.24 — I-8 362.1 2.21 — I-11 — — Y I-14 376.2 2.56 — I-17 405.13.72 — I-20 362.1 2.54 — I-23 362.1 2.55 — I-29 364.2 3.52 — I-35 406.13.8 Y I-38 376.1 3.13 Y I-41 379.2 3.84 — I-44 391.1 3.84 — I-47 429.14.12 — I-91 429.1 4.12 — I-94 397.1 3.75 —

Example 5 GSK-3 Inhibition Assay

[0157] Compounds were screened for their ability to inhibit GSK3-β (AA1-420) activity using a standard coupled enzyme system (Fox et al.(1998) Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were10 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 60 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[0158] An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. 59 μl of the test reaction was placed in a 96 well ½-diameterplate (Corning, Corning, N.Y.) then treated with 1 μl of a 2 mM DMSOstock containing the test compound (final compound concentration 30 μM).The plate was incubated for ˜10 minutes at 30° C. then the reactioninitiated by addition of 7 μl of ATP (final concentration 10 μM). Ratesof reaction were obtained using a Molecular Devices Spectramax platereader (Sunnyvale, Calif.) over a 5 minute read time at 30° C. Compoundsshowing greater than 50% inhibition versus standard wells containingDMSO, but no compound, were titrated and K_(i) values were determined.

[0159] Table 4 shows the results of the activity of selected compoundsof this invention in the GSK3 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having a K_(i)less than 0.1 micromolar (μM) are rated “A”, compounds having a K_(i)between 0.1 and 1 μM are rated “B” and compounds having a K_(i) greaterthan 1 μM are rated “C”. TABLE 4 GSK3-β Activity of Selected CompoundsNo. I- Activity No. I- Activity No. I- Activity 16 C 19 A 22 A 28 A 31 A34 A 37 A 40 A 43 A 46 A 49 A 52 A 55 A 58 A 61 C 64 C 67 B 73 A 10 C 4A 7 — 25 A 76 A 79 A 82 A 85 A 88 A 100 A 103 A 106 A 109 A 112 A 115 A2 C 5 A 8 A 11 A 14 A 17 A 20 A 23 A 29 A 35 A 38 A 41 A 44 A 47 A 91 A94 A 3 A 6 A 9 A 12 A 15 A 18 A 21 C 24 A 27 A 30 A 33 A 36 B 39 A 42 A45 A 48 A 51 B 54 A 57 A 60 A 63 A 66 A 69 A 72 A 75 A 78 A 81 A 84 A 87A 90 A 93 C 96 C 99 A — — 105 A 108 B 111 A 114 C 117 C — — — —

Example 6 Aurora2 Inhibition Assay

[0160] Compounds are screened in the following manner r ability toinhibit Aurora2 using a standard enzyme assay (Fox et al (1998) ProteinSci 7, To an assay stock buffer solution containing 0.1M 5, 10 mM MgCl₂,1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/mlpyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and 800 μMpeptide (LRRASLG, American Peptide, Sunnyvale, Calif.) is added a DMSOsolution of a compound of the present invention to a final concentrationof 30 μM. The resulting mixture is incubated at 30° C. for 10 minutes.The reaction was initiated by the addition of 10 μL of Aurora2 stocksolution to give a final concentration of 70 nM in the assay. The ratesof reaction are obtained by monitoring absorbance at 340 nm over a 5minute read time at 30° C. using a BioRad Ultramark plate reader(Hercules, Calif.). The IC₅₀ values are determined from the rate data asa function of inhibitor concentration.

[0161] Table 5 shows the results of the activity of selected compoundsof this invention in the Aurora2 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having an IC₅₀less than 0.5 micromolar (μM) are rated “A”, compounds having an IC₅₀between 0.5 and 2 μM are rated “B” and compounds having an IC₅₀ greaterthan 2 μM are rated “C”. TABLE 5 Aurora2 Activity of Selected CompoundsNo. I- Activity No. I- Activity No. I- Activity 2 C 4 B 5 C 7 C 8 A 10 C11 A 13 C 14 B 16 A 17 A 19 B 20 A 22 A 23 A 25 B 26 A 28 C 29 A 31 A —— 34 A 35 C 37 B 38 A 40 C 41 C 43 C 46 C 49 B 50 B 52 C 55 A 56 B 58 C59 C 61 C 62 B 64 C 67 A 70 B 73 A 76 C 79 C 82 C 85 C 88 B 91 C 94 A 97C 100 C 103 C 106 C 109 C 112 C 114 B — —

Example 7 Syk Inhibition Assay

[0162] Compounds were screened for their ability to inhibit Syk using astandard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).Reactions were carried out in 100 mM HEPES pH 7.5, 10 mM MgCl₂, 25 mMNaCl, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in theassay were 200 1 μM ATP (Sigmachemical Co.) and 4 μM poly Gly-Tyrpeptide (Sigma Chemical Co.). Assays were carried out at 30° C. and 200nM Syk. Final concentrations of the components of the coupled enzymesystem were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvatekinase and 10 μg/ml lactate dehydrogenase.

[0163] An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of Syk, DTT and the testcompound of interest. 56 μl of the test reaction was placed in a 96 wellplate followed by the addition of 1 μl of 2 mM DMSO stock containing thetest compound (final compound concentration 30 μM). The plate waspre-incubated for ˜10 minutes at 30° C. and the reaction initiated bythe addition of 10 μl of enzyme (final concentration 25 nM). Rates ofreaction were obtained using a BioRad Ultramark plate reader (Hercules,Calif.) over a 5 minute read time at 30° C. Compounds showing >50%inhibition versus standard wells containing DMSO, but no compound, weretitrated and IC50's determined using a similar protocol.

[0164] Table 6 shows the results of the activity of selected compoundsof this invention in the Syk inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having an IC₅₀less than 0.5 micromolar (μM) are rated “A”, compounds having an IC₅₀between 0.5 and 2 μM are rated “B” and compounds having an IC₅₀ greaterthan 2 μM are rated “C”. TABLE 6 Syk Activity of Selected Compounds No.I- Activity No. I- Activity No. I- Activity 2 C 4 B 5 A 7 A 8 C 11 A 14B 16 B 17 A 19 B 22 A 23 A 25 A 29 A 31 A 34 A 35 C 37 A 38 A 43 C 44 A46 C 47 C 49 C 50 A 52 C 53 B 55 A 56 B 58 C 59 C 61 C 62 A 64 C 67 A 73A 76 C 82 C 88 C 91 C 94 A 106 C 109 C 112 C 115 C

[0165] While we have described a number of embodiments of thisinvention, it is apparent that our basic examples may be altered toprovide other embodiments that utilize the compounds and methods of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments that have been represented by way of example.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein: R¹ isselected from R, halogen, CN, NO₂, or TR; T is an optionally substitutedC₁-C₄ alkylidene chain wherein up to two methylene units of T areoptionally and independently replaced by O, N(R), C(O), S, SO, or SO₂;each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein: two R bound to the samenitrogen atom are optionally taken together with the nitrogen to form a3-7 membered saturated, partially unsaturated, or fully unsaturated ringhaving 0-2 heteroatoms, in addition to the nitrogen bound thereto,independently selected from nitrogen, oxygen, or sulfur; Ar¹ is anoptionally substituted ring selected from: (a) a 3-8 membered monocyclicor 8-10 membered bicyclic saturated, partially unsaturated, or arylring; (b) a 3-7 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar¹ is optionally substituted by one to four substituentsselected from the group consisting of: (a) one group selected from QR.Ar², or QAr²; and (b) up to four R² groups; each Q is independentlyselected from a valence bond or an optionally substituted C₁₋₆alkylidene chain, wherein: one or two non-adjacent methylene units of Qare optionally and independently replaced by —O—, —S—, —NR—, —C(O)—,—CO₂—, —C(O)NR—, —OC(O)NR—, —C(O)C(O)—, —NRC(O)—, NRCO₂—, —NRC(O)NR—,—S(O)—, —SO₂—, —NRSO₂—, —SO₂NR—, or —NRSO₂NR—; each Ar² is an optionallysubstituted ring independently selected from: (a) a 3-8 memberedmonocyclic or 8-10 membered bicyclic saturated, partially unsaturated,or aryl ring; (b) a 3-7 membered heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur; or(c) a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein: Ar² is optionally substituted by one to four R2 groups;and each R² is independently selected from R, halogen, NO₂, CN, OR, SR,N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂, OC(O)N(R)₂, SOR,SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, or C(O)CH₂C(O)R; wherein:two R² on adjacent positions on Ar¹ or Ar² are optionally taken togetherto form a saturated, partially unsaturated, or fully unsaturated 4-6membered ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; provided that: (a) when Ar¹ is phenyl, twoR² are not simultaneously OR in the meta and para positions of Ar¹; and(b) R¹ is other than CN.
 2. The compound according to claim 1, whereinAr¹ is a ring selected from: (a) a phenyl, indanyl, or naphthyl ring;(b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic heteroaryl ring having 1-2 nitrogens, wherein: Ar¹is substituted by one to four substituents selected from the groupconsisting of: (a) one group selected from QR, Ar², or QAr²; and (b) upto four R² groups.
 3. The compound according to claim 2, wherein: Ar¹ isselected from a phenyl, indanyl, naphthyl, pyrimidinyl, or pyridyl ring.4. The compound according to either of claims 2 or 3, wherein: Ar¹ issubstituted by one to four substituents selected from the groupconsisting of: (a) one group selected from QR or QAr²; and (b) up tofour R² groups; wherein: each R² is independently selected from halogen,CN, CO₂R, R, NO₂, OR, haloalkyl, SO₂N(R)₂, or N(R)₂; each Q isindependently selected from a C₁₋₄ alkylidene chain wherein one or twomethylene units of Q are optionally replaced by O, NH, NHCO, NHCO₂,NHSO₂, or CONH; and Ar is is a 3-6 membered carbocyclic ring or anoptionally substituted phenyl or 5-6 membered heterocyclic or heteroarylring having one to two heteroatoms independently selected from nitrogen,oxygen, or sulfur.
 5. The compound according to either of claims 2 or 3,wherein: Ar¹ is substituted by Ar² and optionally substituted with 1-2R² substituents, wherein: each Ar² is an optionally substituted ringindependently selected from: (a) a phenyl, indanyl, or naphthyl ring;(b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic or 9-10 membered bicyclic heteroaryl ring having 1-2heteroatoms independently selected from oxygen, nitrogen, or sulfur,wherein: Ar² is optionally substituted with 1-2 R² groups; and each R²is independently selected from R, halogen, NO₂, CN, OR, SR, N(R)₂,C(O)R, SO₂N(R)₂, or SO₂R.
 6. A compound selected from the followingTable 1 compounds: Cmpd I- Structure — — 2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

— — 33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

— — 103

104

105

106

107

108

109

110

111

112

113

114

115

116

117


7. A compound selected from the following Table 2 compounds:


8. A composition comprising a compound according to claim 1, in anamount to detectably inhibit GSK3, Aurora2, or Syk protein kinaseactivity, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.
 9. The composition according to claim 8, additionallycomprising an additional therapeutic agent selected from ananti-diabetic agent, a chemotherapeutic or anti-proliferative agent, atreatment for Alzheimer's Disease, a treatment for Parkinson's Disease,an agent for treating Multiple Sclerosis (MS), a treatment for asthma,an agent for treating schizophrenia, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating cardiovascular disease, an agent for treating liverdisease, an agent for treating a blood disorder, or an agent fortreating an immunodeficiency disorder.
 10. A method of inhibiting GSK3,Aurora2, or Syk kinase activity in a biological sample, comprising thestep of contacting said biological sample with: a) a compositionaccording to claim 8; or b) a compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein: R¹ isselected from R, halogen, CN, NO₂, or TR; T is an optionally substitutedC₁-C₄ alkylidene chain wherein up to two methylene units of T areoptionally and independently replaced by O, N(R), C(O), S, SO, or SO₂;each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein: two R bound to the samenitrogen atom are optionally taken together with the nitrogen to form a3-7 membered saturated, partially unsaturated, or fully unsaturated ringhaving 0-2 heteroatoms, in addition to the nitrogen bound thereto,independently selected from nitrogen, oxygen, or sulfur; Ar¹ is anoptionally substituted ring selected from: (a) a 3-8 membered monocyclicor 8-10 membered bicyclic saturated, partially unsaturated, or arylring; (b) a 3-7 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar¹ is optionally substituted by one to four substituentsselected from: (a) one group selected from QR, Ar², or QAr²; and (b) upto four R² groups; each Q is independently selected from a valence bondor an optionally substituted C₁₋₆ alkylidene chain, wherein: one or twonon-adjacent methylene units of Q are optionally and independentlyreplaced by —O—, —S—, —NR—, —C(O)—, —CO₂—, —C(O)NR—, —OC(O)NR—,—C(O)C(O)—, —NRC(O)—, NRCO₂—, —NRC(O)NR—, —S(O)—, —SO₂—, —NRSO₂—,—SO₂NR—, or —NRSO₂NR—; each Ar² is an optionally substituted ringindependently selected from: (a) a 3-8 membered monocyclic or 8-10membered bicyclic saturated, partially unsaturated, or aryl ring; (b) a3-7 membered heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; or (c) a 5-6 memberedmonocyclic or 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar² is optionally substituted by one to four R² groups; andeach R² is independently selected from R, halogen, NO₂, CN, OR, SR,N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂, OC(O)N(R)₂, SOR,SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, or C(O)CH₂C(O)R; wherein:two R² on adjacent positions on Ar¹ or Ar² are optionally taken togetherto form a saturated, partially unsaturated, or fully unsaturated 4-6membered ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 11. A method of treating or lessening theseverity of a GSK3-, Aurora2-, or Syk-mediated disease or condition in apatient, comprising the step of administering to said patient: a) acomposition according to claim 8; or b) a compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein: R¹ isselected from R, halogen, CN, NO₂, or TR; T is an optionally substitutedC₁-C₄ alkylidene chain wherein up to two methylene units of T areoptionally and independently replaced by O, N(R), C(O), S, SO, or SO₂;each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein: two R bound to the samenitrogen atom are optionally taken together with the nitrogen to form a3-7 membered saturated, partially unsaturated, or fully unsaturated ringhaving 0-2 heteroatoms, in addition to the nitrogen bound thereto,independently selected from nitrogen, oxygen, or sulfur; Ar¹ is anoptionally substituted ring selected from: (a) a 3-8 membered monocyclicor 8-10 membered bicyclic saturated, partially unsaturated, or arylring; (b) a 3-7 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar¹ is optionally substituted by one to four substituentsselected from: (a) one group selected from QR, Ar², or QAr²; and (b) upto four R² groups; each Q is independently selected from a valence bondor an optionally substituted C₁₋₆ alkylidene chain, wherein: one or twonon-adjacent methylene units of Q are optionally and independentlyreplaced by —O—, —S—, —NR—, —C(O)—, —CO₂—, —C(O)NR—, —OC(O)NR—,—C(O)C(O)—, —NRC(O)—, NRCO₂—, —NRC(O)NR—, —S(O)—, —SO₂—, —NRSO₂—,—SO₂NR—, or —NRSO₂NR—; each Ar² is an optionally substituted ringindependently selected from: (a) a 3-8 membered monocyclic or 8-10membered bicyclic saturated, partially unsaturated, or aryl ring; (b) a3-7 membered heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; or (c) a 5-6 memberedmonocyclic or 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar² is optionally substituted by one to four R2 groups; andeach R² is independently selected from R, halogen, NO₂, CN, OR, SR,N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R) 2, OC(O)N(R)₂, SOR,SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O) R, or C(O)CH₂C(O)R;wherein: two R² on adjacent positions on Ar¹ or Ar² are optionally takentogether to form a saturated, partially unsaturated, or fullyunsaturated 4-6 membered ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 12. The method according toclaim 11, wherein said GSK3-mediated disease is selected from diabetes,a neurodegenerative disorder, a CNS disorder, Alzheimer's disease,Huntington's, Parkinson's, AIDS associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), stroke, schizophrenia,cardiomycete hypertrophy, a manic depressive disorder, or baldness. 13.The method according to claim 11, wherein said Aurora2-mediated diseaseis selected from cancer.
 14. The method according to claim 11, whereinsaid Syk-mediated disease is selected from an allergic disorder.
 15. Themethod according to claim 11, comprising the additional step ofadministering to said patient an additional therapeutic agent selectedfrom an anti-diabetic agent, a chemotherapeutic or anti-proliferaticagent, a treatment for Alzheimer's Disease, a treatment for Parkinson'sDisease, an agent for treating Multiple Sclerosis (MS), a treatment forasthma, an agent for treating schizophrenia, an anti-inflammatory agent,an immunomodulatory or immunosuppressive agent, a neurotrophic factor,an agent for treating cardiovascular disease, an agent for treatingliver disease, an agent for treating a blood disorder, or an agent fortreating an immunodeficiency disorder, wherein: said additionaltherapeutic agent is appropriate for the disease being treated; and saidadditional therapeutic agent is administered together with saidcomposition as a single dosage form or separately from said compositionas part of a multiple dosage form.